AU2021235395B2

AU2021235395B2 - Controlled release formulations comprising Drotaverine or salt thereof

Info

Publication number: AU2021235395B2
Application number: AU2021235395A
Authority: AU
Inventors: Nishant BERLIA; Sushma Paul BERLIA; Sunder Singh BHANDARI; Anupama Diwan; Gurvinder Singh
Original assignee: Drotastar LLC
Current assignee: Drotastar LLC
Priority date: 2020-03-09
Filing date: 2021-03-09
Publication date: 2025-11-13
Anticipated expiration: 2041-03-09
Also published as: AU2021235395A1; KR20220151678A; CR20220506A; US20230018600A1; IL296132A; BR112022017998A2; CN115279346A; JP2023525202A; CO2022013429A2; JOP20220209A1; MX2022011196A; EP4117638A1; PH12022552355A1; CA3174747A1; WO2021181262A1; CL2022002431A1

Abstract

The present invention provides controlled release formulations comprising Drotaverine or salt thereof or similar active agents which are prone to oxidative/hydrolytic degradation. The invention provides once or twice a day controlled release formulations of Drotaverine or salt thereof which avoids fluctuations of plasma levels, reduces pill burden and side effects owing to simplified dosage schedule, thereby improving patient compliance. The invention also provides methods of preparation of controlled release formulations of Drotaverine or salt thereof. The invention further provides controlled-release formulations of Drotaverine or salt thereof for treating at least one symptom of gastrointestinal, biliary, urological and gynecological disorders characterized by spastic conditions of smooth muscles in a subject.

Description

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CONTROLLED RELEASE FORMULATIONS COMPRISING DROTAVERINE OR SALT THEREOF RELATED APPLICATIONS

This application claims priority to Indian Patent Application No. 202011010072,

filed March 9, 2020, the invention of which is incorporated herein by reference in its

entirety.

FIELD OF THE INVENTION

In some aspects, the present invention relates to controlled release formulations

comprising Drotaverine or salt thereof or similar active agents those are prone to oxidative

and hydrolytic degradation and methods of preparation thereof. In some aspects, the

invention relates to treatment of symptoms of gastrointestinal, biliary, urological and/or

gynaecological disorders characterized by spastic conditions of smooth muscles by

administering the controlled release formulations of the present invention.

BACKGROUND OF THE INVENTION

It is well known in the field of art to prepare formulations which provide controlled

release of pharmacologically active substances on oral administration to humans and

animals. Controlled release (CR) formulations decrease the frequency of administration

required to maintain therapeutically effective plasma drug levels. In addition, by producing

more constant blood levels, such formulations can reduce the large changes in plasma

levels observed between doses. Controlled release formulations are intended to provide a

longer period of pharmacological action after administration than is ordinarily achieved

after administration of immediate-release (IR) dosage forms. Such longer periods of

response provide therapeutic benefits that are not achieved by immediate release

preparations. Furthermore, controlled release preparations result in better patient

compliance.

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Drotaverine HCI HCl (Z)-1-(3,4-diethoxybenzylidene)-6,7-diethoxy-1,2,3,4

tetrahydroisoquinoline] is a benzylisoquinoline derivative, and is an analogue of

papaverine.

NH

The molecular weight of Drotaverine is 397.50 g/mol and the Empirical Formula is

C24H31NO4. Drotaverine is a potent spasmolytic which acts directly on the smooth muscles

by inhibiting phosphodiesterase activity and is devoid of any anticholinergic side effects.

Drotaverine is a selective inhibitor of phosphodiesterase isoenzyme IV and has been found

useful in controlling spastic disorders of smooth muscle. Drotaverine has a dual mechanism

of action. Firstly, it inhibits enzyme phosphodiesterase IV (PDE IV). This causes an

increase in cyclic adenosine monophosphate level (cAMP) in smooth muscles, resulting in

a decrease in concentration of free calcium ions (Ca2). Secondly, it inhibits calmodulin

(CM), which is a calcium binding protein. The decrease in Ca2+ ions along with the

inhibition of calmodulin leads to inhibition of "Calmodulin-Calcium complex" (CM-Ca2)

formation. This process inhibits myosin light chain kinase enzyme (MLCK), leading to

dephosphorylation of the actomyosin phosphate complex and thus causing normalization of

smooth muscles.

Drotaverine is a highly potent and safe antispasmodic (spasmolytic) agent, suitable

for oral and parenteral administration. Drotaverine is currently marketed as a conventional

IR product indicated in spasmodic pain of smooth muscles. It relieves and prevents smooth

muscle spasm of various organs regardless of their function and innervation. Primarily, the

drug alone and in combination is indicated in the treatment of various gastrointestinal,

biliary, urological and/or gynecological disorders characterized by spastic conditions of

smooth muscles.

For example, Drotaverine is indicated in:

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i) spastic conditions of the gastrointestinal tract: irritable bowel syndrome, biliary colics

and spastic conditions of the biliary tract such as cholecystolithiasis, cholecystitis,

cholangitis.

ii) renal colics and spastic conditions of the urogenital tract: nephrolithiasis, ureterolithiasis, pyelitis, cystitis.

iii) spastic conditions of the uterus: dysmenorrhoea, imminent abortion, uterine tetanus.

It is also widely used for augmentation of labor, in the therapy of spastic pain due to

gastric and duodenal ulcer and prior to instrumental diagnostic procedures. The approved

daily doses are 120-240 mg (in 2-3 divided doses) in adults, 40-120 mg (in 2-3 divided

doses) in children between 1-6 years of age and 80-200 mg (in 2-5 divided doses) in

children over 6 years. Due to its non-anticholinergic nature, Drotaverine can safely be

prescribed for a long duration. Drotaverine has been registered in more than 50 countries, in

Europe, Asia, Africa and Central America.

In indications like irritable bowel syndrome (IBS), where pain is the predominant

symptom, antispasmodics have been and remain the main agents for therapy. Drotaverine

exhibits a normalizing effect on intestinal smooth muscle, which helps in alleviating pain

and does not have side effects like anticholinergics. Anticholinergic antispasmodics are

avoided in IBS where constipation is present (IBS-Constipation is a predominant

symptom). Drotaverine brings relief of spasm in IBS by its unique site-specific action and causes

normalization of smooth muscle contraction. Thus, it does not cause constipation, making it

suitable for use in all types of IBS (Diarrhea predominant IBS, Constipation predominant

IBS, and mixed IBS). The antispasmodic Drotaverine has long been used to relieve pain in

Irritable bowel syndrome (IBS). However, there remains an issue that the drug must be

administered 2-3 times a day, which may lead to poor patient compliance and

inconvenience to the patients.

Abdominal pain is a common problem in children. A variety of disorders can cause

acute abdominal pain in children. Drotaverine is an effective and safe pharmaceutical agent

in the management of recurrent abdominal pain of childhood. It is the most commonly used

off-label medication for alimentary tract problems in preschool- and school-aged children.

Drotaverine was associated with improved progress of the first stage of labor without

increasing the feto-maternal compromise among nulliparous women. Drotaverine can be

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considered as an effective and safe pharmaceutical agent to shorten the duration of the first

stage of spontaneous labor among nulliparous women.

Drotaverine is efficient and advantageous in ameliorating and/or treating benign

prostatic hyperplasia, urinary disorders, disorders related to bladder dysfunction, lower

urinary tract symptoms associated or not associated with benign prostatic hyperplasia,

urinary incontinence, bladder outlet obstruction associated or not associated with benign

prostatic hyperplasia, interstitial cystitis and overactive bladder.

Drotaverine contributes very effectively either alone or in combinations in relieving

painful spasm in a wide variety of disease of gastroenterological, urological, gynecological

and/or obstetrical origin and is the first drug of choice in emergency medicine. Drotaverine

does not mask the symptoms of "acute abdomen" and this feature of Drotaverine makes it

unique.

A spasmolytic like Drotaverine and anti-prostaglandin like mefenamic acid may be

used as analgesia in women undergoing IUD (intra-uterine device) insertion in the clinic.

Drotaverine allays early-onset pain and potentiates a sustained analgesic effect of

mefenamic acid. The combination of Drotaverine and mefenamic acid is effective in

decreasing the pain during the procedure and its effect lasts longer than that of paracervical

block or intravenous sedation.

Addition of Drotaverine to Aceclofenac provides significant therapeutic benefits in

relieving pain associated with primary dysmenorrhoea. Drotaverine produces rapid pain

relief due to antispasmodic action while Aceclofenac provides sustained analgesic effect.

The fixed-dose immediate release (IR) combination of Aceclofenac-Drotaverine should

therefore be considered as effective and well tolerated treatment for primary

dysmenorrhoea.

There is a significant decrease in abdominal pain in subjects with acute infectious

gastroenteritis when treated with Drotaverine hydrochloride (80 mg) and Paracetamol

(PCM) 500 mg as compared to subjects treated with PCM alone, demonstrating the

effectiveness of a fixed dose IR combination of Drotaverine hydrochloride (80 mg) and

PCM (500 mg) for amelioration of abdominal pain associated with acute infectious

gastroenteritis.

Some other possible combinations with Drotaverine have been studied in the literature:

WO2016075617 discloses that a combination of an analgesic and an anti-spasmodic

agent such as ibuprofen (400 mg) and Drotaverine (80 mg) for treating menstrual and

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abdominal cramps alleviates the pain associated with menstruation and relieves abdominal

cramps.

Zhu, J. et al (2017) discloses that a combined therapy of ketorolac, diclofenac, and

Drotaverine is effective in the relief of acute renal colic, especially pain due to mid and

proximal ureteric lithiasis and that this therapy was associated with reduced use of rescue

analgesia.

All of these marketed combinations with Drotaverine are available as immediate

release dosage forms and none of the combinations disclose controlled release preparations.

The pharmacokinetic parameters, such as elimination, half-life, plasma clearance,

renal clearance and apparent volume of distribution of Drotaverine, are not influenced by

the route of drug administration (Bolaji OO et al., 1996). The pharmacokinetic parameters

for immediate release (IR) Drotaverine Tablets 80 mg have been studied. The drug is

mainly eliminated by non-renal routes since renal clearance accounted for only 0.31 +/-

0.13% of the total plasma clearance. The absolute bioavailability was variable and subject-

dependent and ranged between 24.5-91% with a mean of 58.2 +/- 18.2% (mean +/- SD). It

is suggested that high variation in bioavailability of Drotaverine HCI after oral

administration results in significant inter-individual differences in therapeutic response to

the drug. In pharmacokinetic and bioavailability studies, Drotaverine has shown rapid

absorption viz., onset of action within 12 minutes after oral administration of 80 mg

strength IR tablets and almost 90% of drug absorption from small intestine. The peak

plasma levels were obtained after 1 to 3 hours while elimination half-life ranges from 7 to

11.95 hours. Drotaverine seemed to be very safe in toxicological studies as the reported oral

LD50 for Drotaverine is >1000mg/Kg body weight and hence has a wide therapeutic index

(Blasko G, 1996).

CN102149382 provides that Drotaverine in free form or in form of a salt is helpful

in improving and/or treating benign prostatic hyperplasia, urinary disorders, conditions

involving bladder dysfunction, lower urinary tract symptoms associated with or unrelated to

benign prostatic hyperplasia, urinary incontinence, bladder outlet obstruction, interstitial

cystitis, and overactive bladder associated with or unrelated to benign prostatic hyperplasia;

wherein the preferred Drotaverine salt is Drotaverine HCI. The pharmaceutical

compositions provided were suitable for administration by oral or parenteral routes and

may be prepared further for sublingual, subcutaneous, intramuscular, intravenous,

intradermal, topical or rectal administration. The pharmaceutical compositions is prepared

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by incorporation of pharmaceutical additive(s) in a ratio ranging from 1% by weight to 90%

by weight based on the weight of the Drotaverine or its salt. Examples of excipients used in

the preparation of solid pharmaceutical compositions include, for example, lactose, sucrose,

starch, talc, cellulose, dextrin, kaolin, calcium carbonate, and the like.

When preparing a solid composition in the form of a tablet, the active component is

mixed with excipients. The tablets may be coated with sucrose or other suitable materials,

or they may be treated such that they have extended or delayed activity, and they

continuously release a predetermined amount of the active ingredient. A preparation in the

form of gelatin capsules is obtained by mixing the active ingredient with a diluent and by

pouring the mixture obtained into soft or hard gelatin capsules. For the preparation of liquid

compositions for oral administration, use of a conventional inert diluent such as water or a

vegetable oil has been reported. The liquid compositions are disclosed to incorporate, in

addition to the inert diluent, auxiliaries such as moistening agents, suspension aids,

sweeteners, aromatics, colorants, and preservatives. The liquid composition obtained can be

filled in capsules made of an absorbable material such as gelatin. The CN102149382

invention provides Examples of solvents or suspension mediums used for preparation of

compositions for parenteral administration, viz., injections and suppositories include water,

propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin and the like.

Examples of base materials used for suppositories include, for example, cacao butter,

emulsified cacao butter, lauric lipid, witepsol. When the compositions of CN102149382 are

administered in humans by parenteral route or oral route, the daily dose of Drotaverine

varied between 15 to 250 mg; and preferably between 120 to 240 mg. More preferably, the

dose of Drotaverine HCI is 40 mg once to six times per day, or 80 mg, once to three times

per day as immediate release dosage form. The effect of Drotaverine was studied on

induced plateau of contraction in human isolated detrusor muscle. CN102149382 showed

that Drotaverine induces a significant concentration-dependent relaxation of the human

detrusor muscle contraction.

EP2709599 B1 relates to a stable immediate-release pharmaceutical composition of

Drotaverine HCI for oral administration. The document provides a pharmaceutical

composition in form of a soft capsule for oral administration comprising 5 to 30% (w/w) of

Drotaverine HCI; at least 60% (w/w) of a liquid mixture of a non-ionic hydrophilic

surfactant and a nonionic hydrophobic surfactant, wherein the non-ionic hydrophilic

surfactant is polysorbate 80 and the non-ionic hydrophobic surfactant is propylene glycol

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monocaprylate; wherein the weight ratio of Drotaverine HCI to the liquid mixture of

surfactant is from 1:3 to 1:7. EP2709599 B1 addresses a problem with gelatin-based

compositions, which is an apparent fall in dissolution upon aging, attributed to the cross-

linking of gelatin containing products. The cross-linking causes formation of a swollen,

very thin, tough, rubbery, water-insoluble membrane, also known as pellicle. The pellicle

acts as a barrier and restricts release of the drug. Drugs like Drotaverine or its

pharmaceutically acceptable salts or hydrates thereof, have a tendency to react with gelatin

and induce cross linking owing to which the possibility of fall in dissolution during stability

studies is high. EP2709599 B1 provides that such cross linking of gelatin is overcome by

addition of certain weak acids such as tartaric acid, citric acid or its combinations thereof in

combination with glycine; in an amount of about 0.1 to 1.0% on wt. basis of the gelatin

shall formula. Further, the document provides that the preferred gelatin composition for use

in constructing soft gelatin capsules for use with the Drotaverine composition includes

gelatin and a plasticizer(s) like propylene glycol, and sorbitol. The results reveal that 100%

(w/w) of the Drotaverine HCI dissolved is released after 30 minutes for NoSpa tablet and

after 45 minutes for a composition according to EP2709599 B1.

EP1200088A2 relates to an analgestic / antipyretic immediate release composition

in tablet form comprising paracetamol and Drotaverine HCI optionally along with codeine

phosphate as active ingredients in a mixture with one or more organic acid or potassium

sorbate as stabilizers, one or more usually used pharmaceutical auxiliary materials. The

commonly used fillers and vehicles employed were lactose, mannitol, sorbitol, gliders, e.g.,

magnesium stearate, stearic acid and talc, furthermore substances facilitating disintegration,

e.g. poly(vinylpoly-pyrrolidone), starch, cellulose and pigments, e.g., iron(III)-oxides, or

organic dyes. The pharmaceutical compositions of EP1200088A2 optionally employed

saccharide type fillers and an organic acid as stabilizer. The quantity of decomposition

products in the compositions of EP1200088A2 was found to be low even after long time

under the conditions of accelerated and long term stability tests too. The tablets produced

according to EP1200088A2 were reported to be stable from physical and chemical aspects

alike.

Indian Patent Application 1625/DEL/2006, provides solid oral immediate release

pharmaceutical composition containing two therapeutically active agents to be used as a

spasmolytic and analgesic composition. The application provides that spasmolytic drugs

such as Drotaverine are often prescribed with anti-inflammatory agents, whenever there is

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an inflammatory condition associated with the muscle spasms. The application discloses

that the two drugs i.e., ketorolac tromethamine and Drotaverine HCI when formulated into

a dosage form as a mixture undergo a certain amount of degradation. The application

circumvented incompatibility between the drugs by avoiding contact between ketorolac and

Drotaverine and formulating solid oral pharmaceutical composition as a bilayer tablet. The

solid dosage form further comprises a pharmaceutically acceptable carrier, which comprises

one or more of diluent(s), binder(s), dis-integrant(s), glidant(s) and lubricant(s).

RU2535049C1 discloses a process of preparing stabilized Drotaverine hydrochloride. In order to protect Drotaverine hydrochloride from oxidative

decomposition/degradation, Drotaverine hydrochloride is crystallized in the presence of a

stabilizing additive of a mixture of citric acid and its sodium salt in an amount of up to

1.0% of the weight of Drotaverine hydrochloride fed for crystallization. The document

discloses a method for producing a stabilized substance of Drotaverine hydrochloride by

introducing stabilizing additives, characterized in that the stabilizing additives are

introduced into the reaction mass during the process of recrystallization of Drotaverine

hydrochloride from a solution. RU2199308C1 discloses that stabilization of Drotaverine

hydrochloride is carried out by introducing stabilizing additives such as sodium sulfite,

ethyl alcohol etc. in the solution.

WO2019149917A1 discloses immediate release pharmaceutical composition

comprising, in one dosage form, metamizole, Drotaverine, and caffeine, characterized in

that metamizole in the said composition is present in the form of a granulate comprising

metamizole, and Drotaverine and caffeine are present outside the granulate.

WO2019149917A1 provides that the combination of metamizole, Drotaverine, and caffeine

is known for its strong analgesic effect and such a combination can be used in case of

severe and persistent pain and fever. Additionally, the combination of an analgesic

substance (metamizole) with an antispasmodic substance (Drotaverine) effectively relieves

spastic pains occurring during migraine, menstruation, colic, etc. The third active substance

(caffeine) in the composition aids by enabling faster action of the medicine and intensifies

the analgesic effects of the other substances (metamizole and Drotaverine). All the above

cited literature discloses the immediate release preparations and none of them are related to

the controlled release dosage forms of Drotaverine.

Om Prakash et al., 2013 reported the development of floating drug delivery system

containing Drotaverine. The main objective of the study reported by Om Prakash was to

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develop floating tablets of Drotaverine HCI that prolong the gastric residence time with

total floatation time greater than 24 hours. This study also discloses using a combination of

hydrophilic (HPMC) and hydrophobic (carbopol-934P) polymers as essential components

along with Sodium Carbonate and Citric acid as gas forming agents for ensuring 24h drug

release profile. The formulation as per this study shows very slow dissolution with around

50% drug release in 8 hours; 75% drug release in 16 hours and around 99% dissolution in

24 hours. This is merely a research paper and appears to have no industrial applicability.

The objective of this research paper was to increase gastric residence time and there is no

disclosure of viable controlled release formulation. Based on teachings of this prior art, a

person skilled in the art cannot develop a formulation of Drotaverine having controlled

release profile of 12-24 hrs.

Drotaverine HCI is highly susceptible to oxidation. It undergoes oxidative

degradation by oxidative decomposition to Drotaveraldine in neutral or alkaline media,

whereas upon exposure to light, the molecule is degraded to perparin and then to

perparaldin by dehydrogenation.

In compatibility studies, it has been found that the chemical stability of Drotaverine

hydrochloride solid pharmaceutical compositions is significantly influenced by the

moisture content of the tableting excipients, granules and tablets, and the chemistry of the

composition. The available prior art did not give any clue to prepare controlled release

dosage forms of drotaverine which are chemically stable.

The interaction of Drotaverine HCI with a number of tableting excipients like

magnesium stearate (which is widely used in tableting) has been studied and it has been

found that the degradation of Drotaverine HCI is greatly enhanced by its alkaline hydrolysis

especially in presence of moisture. In addition, the chemical instability of Drotaverine

hydrochloride is significantly influenced by the pH of the formulation, and the degradation

rate was largely enhanced in the presence of magnesium stearate. The developed

formulation of current invention surprisingly demonstrates good stability even in the

presence of Magnesium stearate and hence successfully overcame the limitation of adding

Magnesium Stearate as reported in prior art

There also is a need to control moisture content levels to ensure minimal

degradation of Drotaverine HCI in the finished product. Additionally, Drotaverine HCI or

similar type of drug molecules that are sensitive to oxygen may also require encapsulation

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or special coating or a microenvironment with inert gas e.g., nitrogen etc. in the finished

product primary packing to further improve shelf-life.

Perhaps due to very high susceptibility of Drotaverine to oxidative and hydrolytic

degradation, and other reasons, a controlled release (CR) formulation of Drotaverine was

never considered possible or feasible.

The goal of any drug delivery system is to provide a therapeutic amount of drug in

the body to achieve and then maintain the desired drug concentration. Consistent,

prolonged delivery of medicine results in better patient compliance because patients do not

require multiple administrations. Controlled-release formulations are also safer, as there is

decrease of side effects related to dangerous spikes in drug concentrations. There is thus

necessity for a CR formulation with lesser dosing frequency, preferably a single dose per

day. In particular, there is a need in the field of art for an oral formulation of Drotaverine

that provides controlled release of the drug while ensuring rapid onset of action. The

present invention provides CR formulations of Drotaverine or salt thereof that release the

drug from a single ingestible tablet or capsule SO as to release the drug throughout the

course of a day.

One of the embodiments of developed formulations of current invention exhibits

'Biphasic release profile' with the successful incorporation of 'instant and prolonged

'release portions for immediate and sustained pain relief.

References:

1. Bolaji OO, Onyeji CO, Ogundaini AO, Olugbade TA, Ogunbona FA. Pharmacokinetics

and bioavailability of Drotaverine in humans. Eur J Drug Metab Pharmacokinet. 1996;

Jul-Sep; 21(3):217-21.

2. Blasko G. Pharmacology, mechanism of action and clinical significance of a convenient

antispasmodic agent: Drotaverine. J Am Med Assoc Ind. Physicians' Update 1998;

1:63-9.

3. Om Prakash, S Saraf, M Rahman, Neeraj Agnihotri, and Vinay Pathak. Formulation

and Evaluation of Floating Drotaverine Hydrochloride Tablets Using Factorial Design.

Res J Pharm, Bio and Chem Sci, 2003; Oct-Dec; 4(4): 546-555.

4. Zhu, J. & Cao, Y. & Yu, M.-L & Liu, C. & He, W. & Zeng, B. & Li, J. Efficacy and

safety of combination therapy with Drotaverine and ketorolac versus ketorolac mono-

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therapy for acute renal colic: A retrospective study of 322 patients. International Journal

of Clinical and Experimental Medicine. 2017; 10; 3454-3461.

In an embodiment, the present invention provides a controlled-release formulation

of Drotaverine or salt thereof or similar active agents (those are prone to oxidative and

hydrolytic degradation).

In another embodiment, the present invention provides once or twice a day (for

about 12- 24 hours) stable formulations of Drotaverine or salt thereof or similar active

agents (those are prone to oxidative and hydrolytic degradation).

In another embodiment, the present invention provides a stable controlled-release

formulations of Drotaverine or salt thereof with more uniform and predictable oral

bioavailability as compared to formulations of the prior art.

In another embodiment, the present invention provides methods of preparation of

controlled-release formulations of Drotaverine or salt thereof or similar active agents (those

are prone to oxidative and hydrolytic degradation).

In another embodiment the present invention provides a method of treatment of

symptoms of gastrointestinal, biliary, urological and/or gynecological disorders

characterized by spastic conditions of smooth muscles, by administering the controlled

release formulations of the present invention.

Thus, in an important aspect, the present invention provides stable CR

formulation(s) comprising Drotaverine or salts thereof as a once or twice a day dosage

using acidifying agents and polymers. The selected polymers have different hydrophilicity,

hydrophobicity, swelling, erosion and pH dependent solubility characteristics which ensure

flexibility in the control of drug release. The developed CR formulations can be

administered as a multi-layered, multicoated tablet or capsule form. In some embodiments,

the Drotaverine CR formulations disclosed herein can be dosed once a day leading to better

patient convenience and compliance. They can be formulated as a single layer, bilayer or

trilayer tablets or multicoated mini tablets or beads or pellets compressed as MUPS

(Multiple-Unit Pellet System) tablets or filled in capsules. The capsule shells used can be of

gelatin or non-gelatin based materials.

In order to identify the various parameters for a tablet formulation, trials of IR layer

and CR (controlled release) layer were undertaken. The best prototype formulation having

both IR and CR layer was selected on the basis of their dissolution profiles. Various

concentrations of super disintegrants viz. Sodium Starch Glycollate, Croscarmellose Sodium, and Crospovidone were used alone or in combination to improve the IR- layer drug release and different grades of polymers alone or in combination at different concentrations are used to develop the CR-layer. 5 Oral ingestion is the most convenient and commonly employed route of drug delivery due to its ease of administration, high patient compliance, cost effectiveness, least sterility constraints, and flexibility in the design of the dosage form. Drotaverine has a fast 2021235395

onset of action that initiates relief from pain within 12 minutes after oral administration. Thus, an advantage of the compositions and methods of the present invention is to improve 10 disease management by modifying the drug release rate profiles of Drotaverine drug delivery in comparison to IR tablets when administered orally. This will in turn lead to reduction of a dosing frequency from three times a day to once or twice a day, which provides greater convenience and better patient compliance. In another embodiment, Drotaverine CR formulations of the present 15 invention ensure uniform and therapeutically effective predictable plasma concentration level in blood stream for a period of 12-24 hours, thereby avoiding fluctuations of drug plasma level that are normally observed in IR tablet drug therapy. A once a day controlled release formulation also reduces the pill burden to patients. The CR formulations of Drotaverine or salt thereof provided by the present invention are designed in such a way 20 that sufficient amount of the drug is released immediately within the 1st hour to achieve plasma levels similar to the immediate release dosage form, and such that the rest of the drug is gradually released over a period of 24 hours to maintain the drug concentration within the therapeutic window. Thus, the formulations of the present invention assure a rapid and prolonged release of Drotaverine or salt thereof. Drotaverine CR formulations of 25 the present invention avoid fluctuations of plasma levels with reduced side effects due to a simplified dosage schedule, compared with those of immediate-release dosage form, thereby improving patient compliance. It is to be understood that if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms a part of the common 30 general knowledge in the art in Australia or any other country.

12 21982198_1 (GHMatters) P119866.AU 12/08/2025

SUMMARY OF THE INVENTION

5 The present invention relates to CR formulations of Drotaverine or salts thereof or similar antispasmodic agent. the formulations of present invention comprise Drotaverine or salts thereof, one or more polymers and one or more pharmaceutically acceptable excipients 2021235395

12a 21982198_1 (GHMatters) P119866.AU 12/08/2025

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such that when administered orally the formulations release Drotaverine or salts thereof in a

controlled release (CR) manner over a prolonged period of time (e.g., 12-24 hours). The

term "Controlled release" used throughout the specification shall apply to dosage forms,

matrices, particles, coatings, portions thereof, or compositions that alter the release of an

active ingredient in any manner. Types of controlled release include modified, prolonged,

sustained, extended, delayed, and the like.

In some aspects, the present invention relates to once or twice a day controlled

release formulations of Drotaverine or salt thereof which avoid fluctuations of plasma

levels, reduce pill burden and side effects, and which facilitate a simplified dosage

schedule, thereby improving patient compliance. In some embodiments, the formulations

release a sufficient amount of Drotaverine or salt thereof immediately within the 1st hour

after administration to achieve plasma levels similar to a conventional IR dosage form,

thereby rapidly achieving minimal effective concentration (MEC). Thereafter, the drug is

gradually released over a period of 12-24 hours to maintain the drug concentration within

the therapeutic window viz. MEC.

In some embodiments, the CR formulations of the present invention employ

polymers viz., Hypromellose, Hydroxyethyl Cellulose, Hydroxypropyl Cellulose, methyl

cellulose, Carboxymethyl Cellulose or salts thereof, Ethyl Cellulose, Carbomers,

Methacrylic acids and Polyethylene Oxides (non-ionic polymers) alone or in combination,

acrylic copolymers and other tableting excipients and optionally one or more polymers

from above list for film coating of compressed tablets.

In some embodiments, the CR formulations of the present invention also contain

acidifying agents. The acidifying agent can be selected from, for example, Citric acid,

Fumaric acid, Lactic acid, Maleic acid, Malic acid and Tartaric acid, alone or in

combination.

The CR formulations may comprise other pharmaceutically acceptable excipients

including fillers, flow aids, lubricants. Additional ingredients in the developed formulations

may also include stabilizers e.g., acidifying agents, antioxidants etc.

Additionally, Drotaverine HCI or a similar type of drug molecule that is sensitive to

oxygen may also require encapsulation or special coating or a microenvironment with inert

gas e.g., nitrogen etc. in the finished product primary packing to further improve shelf-life.

Suitable examples of drugs that are prone to oxidative degradation are selected from but not

WO wo 2021/181262 PCT/IB2021/051942

limited to Drotaverine, Mebeverine, Alevarine, Papaverine and pharmaceutically acceptable

salts thereof.

Controlled release (CR) formulations deliver drug to body SO as to establish

therapeutically effective blood level of the active ingredient and once the blood level is

achieved they continue to maintain constant blood levels for long durations by delivering

the drug to body at the same rate as the body eliminates the drug. By avoiding peaks and

troughs of the active ingredient in blood level associated with immediate release dosage

forms, controlled drug delivery systems lower the incidence of adverse effects or side

effects. Also, the controlled drug delivery systems reduce the frequency of dosing, leading

to convenience to the patient in terms of dosing and compliance to the specified dosage

regimens.

The present invention also describes CR dosage forms for Drotaverine, which has a

fast (immediate) release fraction, which allows for sufficient concentration of the drug,

Drotaverine, in the blood stream to produce quick therapeutic effect, and a slow

(controlled) release fraction which maintains that therapeutic effect. Thus, in some aspects,

the present invention provides a controlled release dosage form of Drotaverine or salt

thereof such that a sufficient amount of drug is released within about 1 hour after

administration to achieve minimal effective concentration (MEC) levels similar to

immediate release dosage form and such that the rest of the drug is released over a period of

about 12 to 24 hours to achieve therapeutic efficacy as a once or twice a day drug delivery

dosage form.

Further, in some aspects, the invention provides methods of preparation of

controlled-release formulations of Drotaverine or a salt thereof. Also, in some aspects, the

invention further provides controlled-release formulations of Drotaverine or salt thereof for

treating at least one symptom of gastrointestinal, biliary, urological and/or gynecological

disorders characterized by spastic conditions of smooth muscles in a subject.

The embodiments of the present invention are provided herein:

An embodiment of the present invention discloses a controlled-release formulation

comprising Drotaverine or a salt thereof, a polymer or mixture of polymers, and at least one

pharmaceutically acceptable excipient, wherein said formulation comprises at least one

acidifying agent and from 0 to 10% by weight of anti-oxidants.

In another embodiment the present invention discloses that the formulation

comprises about 10 to about 300 mg of Drotaverine or salt thereof.

In yet another embodiment the present invention discloses that the formulation 12 Aug 2025

comprises Drotaverine or salt thereof in the range of 15% to 60% (w/w) of the formulation. In still another embodiment the present invention discloses that the Drotaverine salt in the formulation is Drotaverine hydrochloride. 5 In a still another embodiment the present invention discloses that at least one acidifying agent in the formulation is selected from the group consisting of Citric acid, Fumaric acid, Lactic acid, Maleic acid, Malic acid, Tartaric acid, and a combination thereof. A further embodiment the present invention discloses the polymer or mixture of 2021235395

polymers is selected from the group consisting of Hypromellose, Hydroxyethyl Cellulose, 10 Hydroxypropyl Cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, carboxymethyl cellulose, methyl cellulose, sodium carboxymethyl cel- lulose or salts thereof, Ethyl Cellulose, Carbomers, Methacrylic acids, Polyethylene Oxides (PEO), and a combination thereof. In another embodiment the present invention discloses that the polymer is 15 Polyethylene oxide (PEO). In still another embodiment the present invention discloses that the polymer or mixture of polymers is hydroxypropyl methylcellulose having an apparent viscosity ranging from about 100-150,000 cP, wherein, optionally, the polymer or mixture of polymers is K100, K4M, K15M, K100M, E4M, E10M, Methocel K100M CR, or a combination 20 thereof. In yet another embodiment the present invention discloses that the formulation comprises controlled release polymer in the range of 05% to 30% (w/w) of the formulation. In still another embodiment the present invention discloses that the at least one pharmaceutically acceptable excipient in the formulation is selected from the group 25 consisting of gums, fillers, flow aids, lubricants, disintegrants, diluents, binders, lubricants, glidants, and a combination thereof. In another embodiment the present invention discloses that in the formulation the gums are selected from the group consisting of xanthan gum, karaya gum, locust bean gum, alginic acid, sodium alginate, acrylic polymers, and a combination thereof; the diluents are 30 selected from the group consisting of microcrystalline cellulose, lactose, dicalcium phosphate, starch, and a combination thereof; the binders are selected from the group consisting of starch, polyvinylpyrrolidone, natural or synthetic gum, cellulosic polymers, and a combination thereof; the lubricants and glidants are selected from the group consisting of talc, colloidal silicon dioxide, magnesium stearate, and a combination thereof;

15 21982198_1 (GHMatters) P119866.AU 12/08/2025

WO wo 2021/181262 PCT/IB2021/051942

and the disintegrants are selected from the group consisting of Sodium Starch Glycollate,

Croscar-mellose Sodium, Crospovidone, and a combination thereof.

In another embodiment the present invention discloses that the formulation is for

oral delivery.

In yet another embodiment the present invention discloses that the formulation is a

tablet, mini-tablet, MUPS (Multiple-Unit Pellet System) tablet or capsule.

In still another embodiment the present invention discloses that the formulation is in

the form of single layered, bi-layered, multi-layered, coated, uncoated, or multi-coated

pellets, granulates, or beads, which can be filled into capsules or compressed to tablets.

In still another embodiment the present invention discloses that the formulation

comprises a controlled release portion and an immediate release portion.

In a further embodiment the present invention discloses that the formulation

optionally comprises a functional or non-functional coating.

In another embodiment the present invention discloses that the tablet or capsule is

prepared by a wet granulation, dry granulation/slugging or direct compression process.

In still another embodiment the present invention discloses that the capsule

comprises shells prepared by gelatin or non-gelatin based materials.

In another embodiment the present invention discloses that the formulation releases

Drotaverine or salt thereof for at least 24 hours.

elicits a minimum effective concentration in plasma of a subject similar to conventional

immediate release dosage form within about 1 hour and the rest of the drug is gradually

released over a period of about 12-24 hours to maintain the drug concentration within the

therapeutic window of Drotaverine.

In yet another embodiment the present invention discloses that the formulation has a

dissolution release profile in-vitro of 25% to 40% after about 1 hour, 30% to 50% after

about 2 hours, 40% to 65% after about 4 hours, 60% to 85% after about 8 hours and not

less than about 85% after about 16 hours.

pharmaceutically acceptable excipient.

In another embodiment the present invention discloses that the formulation

comprises about 10 to about 300 mg of Drotaverine or salt thereof.

comprises Drotaverine or salt thereof in the range of 15% to 60% (w/w) of the formulation. In still another embodiment the present invention discloses that the Drotaverine salt in the formulation is Drotaverine hydrochloride. 5 In yet another embodiment the present invention discloses that the polymer or mixture of polymers in the formulation is selected from the group consisting of Hypromellose, Hydroxyethyl Cellulose, Hydroxypropyl Cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, carboxymethyl 2021235395

cellulose, methyl cellulose, sodium carboxymethyl cel-lulose or salts thereof, Ethyl 10 Cellulose, Carbomers, Methacrylic acids, Polyethylene Oxides (PEO), and a combination thereof. In still another embodiment the present invention discloses that the polymer or mixture of polymers in the formulation is hydroxypropyl methylcellulose having an apparent viscosity ranging from about 100-150,000 cP, wherein, op-tionally, the polymer or 15 mixture of polymers is K100, K4M, K15M, K100M, E4M, E10M, Methocel K100M CR, or a combination thereof. In another embodiment the present invention discloses that the formulation comprises controlled-release polymer in the range of 05% to 30% (w/w) of the formulation. In a further embodiment the present invention discloses that the at least one 20 pharmaceutically acceptable excipient in the formulation is selected from the group consisting of gums, fillers, flow aids, lubricants, disintegrants, diluents, binders, lubricants, glidants, and a combination thereof. In another embodiment the present invention discloses that in the formulation the gums are selected from the group consisting of xanthan gum, karaya gum, locust bean gum, 25 alginic acid, sodium alginate, acrylic polymers, and a combination thereof; the diluents are selected from the group consisting of microcrystalline cellulose, lactose, dical-cium phosphate, starch, and a combination thereof; the binders are selected from the group consisting of starch, polyvinylpyrrolidone, natural or synthetic gum, cellulosic polymers, and a combination thereof; the lubricants and glidants are selected from the group 30 consisting of talc, colloidal silicon diox-ide, magnesium stearate, and a combination thereof; and the disintegrants are selected from the group consisting of Sodium Starch Glycollate, Croscar-mellose Sodium, Crospovidone, and a combination thereof. In another embodiment the present invention discloses that the formulation is for oral delivery.

17 21982198_1 (GHMatters) P119866.AU 12/08/2025

WO wo 2021/181262 PCT/IB2021/051942

tablet, mini-tablet, MUPS (Multiple-Unit Pellet System) tablet or capsule.

comprises a controlled release portion and an immediate release portion.

In a further embodiment the present invention discloses that the formulation

optionally comprises a functional or non-functional coating.

therapeutic window of Drotaverine.

less than about 85% after about 16 hours.

An embodiment of the present invention discloses a method of preparing a single-

layer controlled release tablet comprising Drotaverine or a salt thereof, the method

comprising:

(a) sieving and dry mixing Drotaverine or salt thereof with an acidifying agent, polymer

and excipient to obtain a drug-excipient blend;

(b) sieving and mixing extra-granular ingredients with the drug-excipient blend to obtain a

for-mulation;

(c) compressing the formulation to form the tablet.

An embodiment of the present invention discloses a method of preparing a single or

multi-layer tablet comprising Drotaverine or a salt thereof, the method comprising:

and excipient to obtain a dry mix;

(b) granulating the dry mix with a binder solution comprising at least polyvinylpyrrolidone

and isopropyl alcohol to obtain granules;

(c) drying the granules to obtain a desired Loss-on Drying of the dried granules;

WO wo 2021/181262 PCT/IB2021/051942

(d) milling the dried granules followed by sieving to obtain granules of specific size;

(e) sieving extra-granular ingredients followed by mixing with the granules of specific size

to obtain a formulation; and

(f) compressing the formulation to form the tablet.

In yet another embodiment the present invention discloses that the method of

preparing a single or multi-layer tablet comprising Drotaverine or a salt thereof comprises

coating the tablet with one or more functional or non-functional coatings.

An embodiment of the present invention discloses a method of treating at least one

symptom of gastrointestinal, biliary, urological and gynecological disorders characterized

by spastic conditions of smooth muscles, for instance, irritable bowel syndrome, biliary

colics, cholecystolithiasis, cholecystitis, cholangitis, renal colics, nephrolithiasis,

ureterolithiasis, pyelitis, cystitis, dysmenorrhoea, imminent abortion, or uterine tetanus in a

subject in need thereof, comprising administering to the subject the formulations of the

present invention.

In still another embodiment the present invention discloses that the method of

treating at least one symptom of gastrointestinal, biliary, urological and gynecological

disorders characterized by spastic conditions of smooth muscles, in a subject in need

thereof, comprising administering to the subject the formulation of the present invention

wherein the formulation is administered as single layer, bi-layered, multi-layered, uncoated,

coated or multicoated pellets, beads, or granules in tablet or capsule form.

An embodiment of the present invention discloses a use a formulation of the present

invention for treating at least one symptom of a gastrointestinal, biliary, urological or

gynecological disorder characterized by spastic conditions of smooth muscles in a subject,

comprising administering the formulation to the subject.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1: The figure shows a representative release rate profile of a CR formulation of

Drotaverine hydrochloride prepared in accordance with the present invention. The

dissolution profile is shown as % drug release of Drotaverine hydrochloride against time (in

hours).

WO wo 2021/181262 PCT/IB2021/051942

DETAILED DESCRIPTION OF THE INVENTION

A large portfolio of polymers is available for CR drug delivery formulations/systems

along with application expertise to meet specific formulation drug delivery which help

development of new products. The controlled release polymer may be one or more

Hypromellose, Hydroxyethyl Cellulose, Hydroxypropyl Cellulose, Carboxymethyl

Cellulose or salts thereof, Ethyl Cellulose, Carbomers, Methacrylic acids and Polyethylene

Oxides (nonionic polymers) are available in different pharmaceutical grades and offer a

range of CR properties for a variety of dosage forms and processing methods. Variations in

molecular weights and chemical substitutions provide innumerable ways to optimize

formulation performance. Each range has fundamentally different hydrophilicity,

hydrophobicity, wettability, pH dependent solubility, swelling and erosion characteristics to

provide flexibility in control of the main mechanisms of release.

In some embodiments, the CR formulations of the present invention contain

Fumaric acid, Lactic acid, Maleic acid, Malic acid and Tartaric acid, or combinations

thereof.

In some embodiments, the CR formulations of the present invention include

Drotaverine or salts thereof, one or more hydrophilic polymers and one or more

pharmaceutically acceptable excipients such that when administered orally the formulations

release Drotaverine in a CR manner over a prolonged period of time.

In some embodiments, the formulations disclosed herein show an in vitro

dissolution profile of Drotaverine or salts thereof, when measured using USP II Method, at

about 75 rpm, in about 1000 ml, 0.1 N HCI (pH 1.2), at about 37=0.5° C, to be between

about 25% and about 40% released after about 1 hour, between about 30% and about 50%

released after about 2 hours, between about 40% and about 65% released after about 4 hours, and between about 60% and about 85% released after about 8 hours and NLT (not

less than) about 85% after about 16 hours. In some embodiments, the formulation releases a

sufficient amount of Drotaverine drug which allows for sufficient concentration of the drug

in the blood stream to produce a quick therapeutic effect and thereafter provides uniform

and slow drug release for about 16 hours which then maintains that effect for about 24

hours duration. Hence, in some embodiments, the present invention provides a modified

release dosage form which would release about 20% of the drug within about 1 hour and the balance of about 80% would be released thereafter to ensure therapeutic action for about 12 Aug 2025

24 hours as a once or twice a day drug delivery dosage form. In some embodiments, the oral controlled release dosage formulations include polymers of low molecular weight polyethylene oxide (PEO) alone or in combination with 5 hydroxypropylmethylcellulose (HPMC) with a non-ionic polymer and other tableting excipients and optionally one or more enteric polymers. Thus, in some embodiments, the CR formulations of the present invention comprise the following: 2021235395

 Drotaverine or its salts thereof, in the range of between about 10 to about 300 mg, e.g., 10 about 40 to about 240 mg. Drotaverine is preferably present in an amount suitable for single or twice a day dosing.  One or more active ingredients which are similar types of drug molecules in that they are sensitive to oxidative degradation. Non-limiting examples of drugs that are prone to oxidative degradation include Drotaverine, Mebeverine, Alevarine, Papaverine and 15 pharmaceutically acceptable salts thereof.  Disintegrants/Superdisintegrants viz. Sodium Starch Glycollate, Croscarmellose Sodium, and Crospovidone, may be selected alone or in combination to improve the IR- layer drug release.  Polyethylene oxide (PEO) as a non-ionic homopolymer of ethylene oxide (CAS Registry 20 Number 25322-68-3). PEO is chemically similar to polyethylene glycol, but has a high molecular weight in the range of 100,000 to 7 million g/mol. Pharmaceutical grades of PEO may have unique properties such as non-ionic, highly swelling, hydrophilic and thermoplastic behaviour. PEOs are safe, non-toxic polymers that are not absorbed through the gastro-intestinal tract. PEO has an IID (Inactive Ingredient Database) limit of 25 about 543.9 mg per tablet for oral applications.  The “hydrophilic controlled-release polymer” may be selected, for instance, from one or more of cellulose derivatives selected from hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose; 30 and gums selected from xanthan gum, karaya gum, locust bean gum, alginic acid and sodium alginate and acrylic polymers. The hydroxypropyl methylcellulose may be, for example, the commercially available products such as Methocel® premium product grades having specific apparent viscosities, e.g., viscosities ranging from about 100- 150,000 cP (2% in water at 20° C) such as K100, K4M,

21 21982198_1 (GHMatters) P119866.AU 12/08/2025

WO wo 2021/181262 PCT/IB2021/051942

K15M, K100M, E4M, E10M; viscosities ranging from 80000-120,000 cP (2% in water

at 20° C) such as Methocel K100M CR. It was observed that the amount of the hy-

drophilic polymer per unit dose of Drotaverine or salt thereof plays a major role in the

release characteristic of the formulation. The amount of hydrophilic controlled-release

polymer may range from about 05-30%w/w per unit weight of dosage form.

The formulations may contain other release-retarding agents including hydrophobic

polymers along with the combination of one or more hydrophilic polymers. However,

hydrophilic polymers alone also can be used to obtain the controlled -release formula-

tions with desirable characteristics achieved by the formulations disclosed herein.

The controlled release formulation may also contain "pharmaceutically acceptable ex-

cipients" selected from, for example, one or more of diluents, binders, lubricants and

glidants.

The diluent may, for example, be selected from, for example, one or more of microcrys-

talline cellulose, lactose, dicalcium phosphate and starch.

The binder may be selected from, for example, one or more of starch, polyvinylpyrroli-

done, natural or synthetic gum and cellulosic polymers.

The lubricants and glidants may be selected from, for example, one or more of talc, col-

loidal silicon dioxide and magnesium stearate.

To protect Drotaverine hydrochloride from oxidative degradation, the developed formu-

lations contain acidifying agents.

The acidifying agent can be selected from, for example, alone or combination of Citric

acid, Fumaric acid, Lactic acid, Maleic acid, Malic acid and Tartaric acid.

The antioxidant can be selected from, for example, alone or combination of butylated

hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sodium metabisulfite, sodium

thiosulfate, propyl gallate, ascorbic acid and cysteine.

In some embodiments, the CR formulations of Drotaverine or salt thereof may be

obtained in form of tablet, bead, pellet or capsule. The tablet may be an uncoated tablet,

coated tablet, or mini-tablets. For instance, the CR formulations may be a single layer

matrix tablet or bi-layer, tri-layer or multi-layered tablets with or without a functional or

non-functional coating. A functional film coating is a coating that has a direct influence on

the drug release of API (active pharmaceutical ingredient) of the solid oral dosage form

(e.g. tablet, capsule, granule or pellet) examples include Ethyl cellulose dispersion with

soluble polymer or enteric polymer based dispersion with water soluble ingredients. While

WO wo 2021/181262 PCT/IB2021/051942

a non-functional film coating is not directly influence the drug release of the API. The

examples include HPMC based film costing dispersion with or without flavour to enhance

the product acceptability of bitter tasting drugs like Drotaverine. The tablet may be

prepared by wet granulation, dry granulation/slugging, or direct compression processes.

The input raw materials are selected to ensure there is minimal level of free water,

which can be detrimental in causing degradation of Drotaverine hydrochloride. The

manufacturing process, especially wet granulation process, required studies may be

performed to adjust the levels of residual moisture content in the final drug product.

In some embodiments, the compressed tablets may be coated with suitable film

forming compositions.

Based on the properties of Drotaverine IR tablets known in the field of art, the

theoretical but hitherto unmet drug release pattern depicting bioavailability and

pharmacokinetic properties for a 'once-a-day dosage form' of Drotaverine would be as

follows:

Time (hours) % Release (Range)

1 25-40

2 30-50

4 40-65

8 60-85

16 NLT 85

The inventors of the present invention undertook several formulation trials

comprising of one or combination of CR polymer, filler and other pharmaceutical auxiliary

components and tried dry and wet granulation manufacturing process to arrive at the CR

release formulations of Drotaverine or salt thereof described above. Initial experiments

were undertaken as a monolayer and bi-layered tablet formulations. However, despite

executing several trials, it was really difficult to control release profile as per theoretical

release pattern which is evident in the following Tables 1 and 2 for monolayer tablets and

Tables 3 and 4 for bi-layer tablets.

Table 1: Mono-layer tablet formulations prepared by different manufacturing

processes

Batch No. DTV-01 DTV-02 DTV-03 DTV-04 DTV-05 DTV-09 Mfg Process Slugging Slugging Slugging Wet gran. Wet gran. Wet gran. (DG) (DG) (DG) (IPA) (IPA) (IPA)

Material Percent (%)

Drotaverine 26.7 26.7 26.7 26.7 26.7 53.3 Hydrochloride

Polyox WSR 50 45 15 303 Methocel - - -- 15 10 HPMC HPMC KK 15 15M M Polyox WSR 20 14.9 301 45 10 23.3 18.3 11.1 MCC -

Methocel 27.3 22.3 17.3 20 15 HPMC K 100 M PVP K-30 4 4 6 IPA

5 5 3.3 MCC Colloidal 0.5 0.5 0.5 0.5 0.5 0.7 Silicon

dioxide

Lubrication

Magnesium 0.5 0.5 0.5 0.5 0.5 0.7 Stearate

Table-2: Dissolution Release profile of mono-layer tablet formulations of Table 1

Dissolution Release profile

Time % % % % % (Target Release) % Batch No. DTV-01 DTV-02 DTV-03 DTV-04 DTV-05 DTV-09

1 hour (25-40%) 7 5 6 6 6 10

2 hours (30-50%) 12 8 9 11 10 18

4 hours (40-65%) 26 18 16 16 23 19 38

WO wo 2021/181262 PCT/IB2021/051942

8 hours (60-85%) 61 40 40 40 54 37 73

16 hours (NLT: 85%) 100 100 100 100 100 100

Table-3: Bi-layer tablets formulations

Component Batch No. (% w/w)

DTV-15 DTV-42 DTV-45 DTV-56 DTV-57

Drug 36 40 40 40 40

CR Polymer 45 36 22.5 13 29

Filler 14 15 26 37 21 26

Binder 4.7 5 6 5 4

Flow aid 0.5 1 1 1 1

Disintegrant 1 1.5 3 - 3

Stabilizer 3 1 - 2 2

Colorant 0.02 0.02 0.02 0.02 0.02

Table-4: Dissolution Release profile of bi-layer tablet formulations of Table 2

Time Target release (%) (%) (%) (%) (%)

(hours) Range (%)

Batch No. DTV-15 DTV-42 DTV-45 DTV-56 DTV-57

1 25-40 36 24 25 20 20 20

2 30-50 45 40 39 33 32

4 40-65 59 41 47 45 41

8 60-85 93 51 53 63 59

16 NLT 85% 100 66 70 86 84

Subsequently, few of these trial batch tablets were exposed to accelerated stability

conditions and evaluated for impurity profiling. For understanding chemical degradation

characteristics of the CR formulations, a prototype formulation was exposed to 'forced

WO wo 2021/181262 PCT/IB2021/051942

degradation studies' and results are presented in below Table 5. It was observed that there

were unknown impurities at levels of nearly 2-3% w/w for accelerated condition exposed

samples. Therefore, in order to develop stable CR formulations with desired profile, pre-

formulation studies of Drotaverine drug characteristics were undertaken to determine some

of key physicochemical properties such as solubility, dissolution, assay and related

substances parameters and drug stability characteristics etc.

Table 5: Chemical degradation characteristics of proposed CR formulation exposed to

" Forced/accelerated degradation studies'

Batch No. DTV-042 DTV-042 DTV-042 DTV-042 ACID BASE PEROXIDE Condition CONTROL Degradation Degradation Degradation Name of RRT % RRT % RRT % RRT % Impurity w/w w/w w/w w/w Drotaverine

Amine Drotaverine No impurities observed Acid Drotaverine

Amide Drotaverladine 1.67 0.02 1.67 0.03 1.67 1.08 1.66 0.91 Highest individual 0.20 0.20 0.20 3.15 unknown impurity Total Impurities 0.51 0.76 1.89 24.58 24.58

The results of the study were most surprising. In view of the fact that Drotaverine is

susceptible to oxidative and hydrolytic degradation, it was assumed that adding an

antioxidant would increase the stability thereof. However, addition of an antioxidant

improved the stability only marginally. On the contrary, and to the utmost surprise of the

inventors, addition of an acidifying agent resulted in remarkable improvement in stability

resulting in a controlled release formulation of Drotaverine. The study demonstrates that

incorporation of small amount of antioxidant to obtain stable CR release formulations is

advantageous in order to avoid oxidative degradation of Drotaverine or salt thereof or

active agents which are prone to oxidative/hydrolytic degradation. Additionally, the results

WO wo 2021/181262 PCT/IB2021/051942

indicate that addition of an acidifier alone or in combination with minor amounts of

antioxidant also helps in developing stable CR formulation of Drotaverine and salt thereof.

The inventors of present invention surprisingly found that stable CR dosage

formulations of Drotaverine or salt thereof with reduced degradation (and having 12-24

hours duration of release profile) can be achieved only with addition of acidifying agent

and without or with minor amounts of antioxidant. The inventors further developed

different CR formulations as monolayer or multilayer; MUPS tablets, coated, uncoated,

tablets, as pellets or mini-tablets filled in capsules. These developed tablets may be coated

with non-functional or functional coating. The capsule shells are based on gelatin or non-

gelatin polymer. The formulations of the present invention can be tablets or capsules

containing immediate and prolonged release portions demonstrating biphasic drug release

profile. This ensures instant bioavailability similar to IR tablets, which is particularly

desirable in the case of patients suffering from pain conditions. The IR portion comprises a

mixture of excipients and stabilizers and suitable quantity of active substance allowing

immediate release action similar to IR tablets along with CR drug portion comprising

appropriate quantities of polymers, excipients and stabilizers interspersed with suitable

portion of active drug ensuring medicament release in a controlled manner over 12-24

hours duration.

The present invention provides a controlled-release formulation comprising

Drotaverine or salt thereof, at least one acidifying agent and a polymer or mixture of

polymers along with at pharmaceutically acceptable excipients wherein said formulation is

substantially free of anti-oxidants. The anti-oxidant may be present from 0 to 10% (w/w) of

the formulation.

Exemplary CR formulations of the present invention are provided in Table 6 with %

range of respective ingredients as per developed formulations.

Table 6: Exemplary CR formulations of the present invention

Component % w/w range

Active Drug 15-60

Filler 13-55

Colorant 0.1-0.6

WO wo 2021/181262 PCT/IB2021/051942

Stabilizer 0.5-10

Binder 3-9

Disintegrant 0.5-8

Flow aid 0.2-1.5

Lubricant 0.2-2

CR Polymer 5-30 5-30

The developed CR formulations were prepared in different dosage forms viz. tablets

or capsules prepared by direct blending, direct compression, dry granulation or wet

granulation-based technology. For wet granulation manufacturing process, the granulating

fluid may be hydro-alcoholic or non-aqueous granulating fluid viz. alcoholic solvents.

The method of preparing a single-layer controlled release tablet comprising

formulation of Drotaverine or salt thereof comprises (a) sieving and dry mixing active

ingredients with acidifying agent, polymer and excipient to obtain drug-excipient blend; (b)

sieving and mixing extra-granular ingredients with the drug-excipient blend obtained in

step (a); (c) compressing the formulation of step (b) to form the tablet.

The method of preparing single or multi-layered tablet comprising Drotaverine or

salt thereof, the method comprising: (a) sieving and dry mixing active ingredients with

acidifying agent, polymer and excipient to obtain dry mix;(b) granulating dry mix by binder

solution comprising at least polyvinylpyrrolidone and isopropyl alcohol to obtain granules;

(c) drying granules to obtain desired Loss-on Drying of dried granules; (d) milling dried

granules followed by sieving to obtain granules of specific size; (e) sieving extra-granular

ingredients followed by mixing with granules obtained in step 'd'; (f) compressing the

formulation of step (e) to form the tablet.

The following non-limiting examples further illustrate the CR formulations of

Drotaverine or salt thereof, and process of making such formulations.

EXAMPLE 1: EXAMPLE 1:

Drotaverine CR formulations prepared as 'Single Layer' tablets by Direct

Compression method in following manner:

Ingredient

%w/w Dry mixing Drotavarine HCI HCl 26.7 Non-ionic poly (ethylene oxide) polymer (Polyox 10 WSR 301) Water-soluble high molecular weight poly(ethylene oxide) polymer (Polyox WSR 303) 45

17.3 MCC Extra-granular Colloidal silicon dioxide 0.5

Magnesium stearate 0.5

EXAMPLE 2:

Drotaverine CR formulation prepared as 'Single Layer , tablets by Wet Granulation

method in the following manner:

Ingredient

%w/w Dry mixing

Drotavarine HCI 26.67

15 HPMC K 15 10 HPMC K 100 Polyox WSR 303 20

18.3 MCC Binder Preparation q.s. IPA

PVP K 30 4

Extra-granular 5 MCC Colloidal silicon dioxide 0.5

Magnesium stearate 0.5 wo 2021/181262 WO PCT/IB2021/051942

EXAMPLE 3: Drotaverine CR formulation prepared as 'Bi-Layer' tablets by Wet Granulation

method:

Ingredient Bi-layered

IR portion CR portion

%w/w %w/w Dry mixing Drotavarine HCI HCl 54.55 52.94

HPMC K 100 - 17.65

Polyox WSR 301 - 17.65 Sodium starch glycolate 3.64 -

31.8 5.88 MCC Brilliant Blue 0.2 -

Binder Preparation IPA q.s. q.s.

PVP K 30 4.5 3.53

Extra granular 4.5 1.47 MCC Colloidal silicon dioxide 0.5 0.5 0.44 Magnesium stearate 0.5 0.44

EXAMPLE 4:

Drotaverine CR formulation prepared as 'Bi-Layer' tablets by Wet Granulation

method:

Ingredient Bi-layered

IR portion CR portion

%w/w %w/w Dry mixing Drotavarine HCI 40 40 40 40 HPMC K 100 - 22.44

Polyox WSR 303 - 22.44

Sodium starch glycolate 4.8 - -

42 7.56 MCC Brilliant Blue 0.2

WO wo 2021/181262 PCT/IB2021/051942

Binder Preparation IPA q.s. q.s.

PVP K 30 6 4.67

Extra-granular 6 2 MCC Colloidal silicon dioxide 0.6 0.44 Magnesium stearate 0.6 0.44

EXAMPLE 5:

Drotaverine CR formulation prepared as 'Bi-Layer' tablets by Wet Granulation

method: 5 method:

Ingredient Bi-layered

IR portion CR portion

%w/w %w/w Dry mixing Drotavarine HCI 46.67 37.78

HPMC K 100 - 22.44

Polyox WSR 303 - 22.44 Sodium starch glycolate 4.8 -

35.3 9.78 MCC Brilliant Blue 0.2 -

Binder Preparation IPA q.s. q.s.

PVP K 30 6 4.67

Extra-granular 6 2 MCC Colloidal silicon dioxide 0.6 0.44

Magnesium stearate 0.6 0.44

Optionally the compressed tablet can be coated with functional and non-functional

coating agents.

EXAMPLE 6:

Drotaverine CR formulation prepared as 'Bi-Layer' tablets by Wet Granulation

method (60 mg strength)

WO wo 2021/181262 PCT/IB2021/051942

Bi-layered

IR portion CR portion Ingredient mg mg Dry mixing Drotavarine HCI 15 45

HPMC K 100 - 25 Polyox WSR 303 - 25 Sodium starch glycolate 2 - -

16 9 MCC Brilliant Blue 0

Binder Preparation IPA IPA q.s. q.s.

PVP K 30 2 5

Extra-granular 2 2 MCC Colloidal silicon dioxide 0.2 0.5

Magnesium stearate 0.2 0.5

EXAMPLE EXAMPLE 7: 7:

Drotaverine CR formulation prepared as 'Bi-Layer' tablets by Wet Granulation

method (120 mg strength)

Bi-layered

IR portion CR portion Ingredient mg mg Dry mixing Drotavarine HCI 30 90

HPMC K 100 - 50 Polyox WSR 303 - 50 Sodium starch glycolate 4 -

32 17 17 MCC Brilliant Blue 0.2

Binder Preparation IPA IPA q.s. q.s.

PVP K 30 5 11

Extra-granular

MCC Colloidal silicon dioxide 1 0.4 1 Magnesium stearate 0.4

EXAMPLE 8: EXAMPLE 8:

Drotaverine CR formulation prepared as 'Bi-Layer' tablets by Wet Granulation

method (180 mg strength)

Bi-layered

IR portion CR portion Ingredient mg mg Dry mixing Drotavarine HCI 45 135

HPMC K 100 - 76 Polyox WSR 303 - 76 Sodium starch glycolate 5 -

47 26 MCC Brilliant Blue 0 Binder Preparation IPA IPA q.s. q.s.

PVP K 30 7 16

Extra-granular 7 7 MCC Colloidal silicon dioxide 1 2 1 Magnesium stearate 2

EXAMPLE 9: EXAMPLE 9:

Drotaverine CR formulation prepared as 'Bi-Layer' tablets by Wet Granulation

method (240 mg strength).

Bi-layered

IR portion CR portion Ingredient mg mg Dry mixing Drotavarine HCI 60 180

WO wo 2021/181262 PCT/IB2021/051942

HPMC K 100 - 100.96

Polyox WSR 303 - - 100.96

Sodium starch glycolate 7.2 -

63.2 34 MCC Brilliant Blue 0.32

Binder Preparation IPA q.s. q.s. IPA PVP K 30 9 21

Extra-granular 9 9 MCC MCC Colloidal silicon dioxide 0.8 2 Magnesium stearate 0.8 2

EXAMPLE 10:

Drotaverine CR formulation granules prepared by Wet Granulation method (240 mg

strength)

IR Portion CR Portion Ingredients (in mg) (in mg) Intra-granular Material Drotaverine HCI 75.00 165.00

Sodium Starch Glycollate 7.00 35.70 133.60 MCC 54.00 HPMC K 100M -

54.00 HPMC K 4M -

Colloidal Silicon Dioxide - 2.00 Colouring agent 0.20 -

Binder Solution Citric Acid 3.60 8.40

IPA q.s. IPA q.s.

PVP K 30 9.00 25.00

Extra-granular Material 18.00 5.00 MCC Colloidal Silicon Dioxide 0.45 1.00 Colouring agent 0.15

Magnesium Stearate 0.90 2.00

WO wo 2021/181262 PCT/IB2021/051942

EXAMPLE 11:

Drotaverine CR formulation granules prepared by Wet Granulation method (240 mg

strength)

IR Portion ER Portion Ingredients (in mg) (in mg)

Intra-granular Material Drotaverine HCI 60.00 180.00 Sodium Starch Glycollate 7.00 -

23.40 186.10 MCC HPMC K 100M - 38.40 38.40 38.40 HPMC K 4M -

Colloidal Silicon Dioxide - 2.00

Colouring agent 0.20 -

Sodium Metabisulfite 0.90 2.1

Binder Solution

IPA q.s. q.s.

PVP K 30 9.00 25.00 25.00 Extra-granular Material 18.00 5.00 MCC Colloidal Silicon Dioxide 0.45 1.00 Colouring agent 0.15 -

Magnesium Stearate 0.90 2.00

EXAMPLE 12:

Drotaverine CR formulation granules prepared by Wet Granulation method (240 mg

strength)

IR Portion ER Portion Ingredients (in mg) (in mg)

Intra granular Material

Drotaverine HCI 60.00 180.00

Sodium Starch Glycollate 7.20 -

60.80 29.50 MCC HPMC K 100M - 100.96

WO wo 2021/181262 PCT/IB2021/051942

Polox WSR 303 -- 100.96

Colloidal Silicon Dioxide - 2.00

Colouring agent 0.20 - -

Sodium Metabisulfite 1.50 4.5

Binder Solution

IPA IPA q.s. q.s.

PVP PVP KK 30 30 9.00 21.00

Extra granular Material

9.45 7.08 MCC Colloidal Silicon Dioxide 0.80 2.00

Colouring agent 0.15 -

Magnesium Stearate 0.90 2.00

EXAMPLE 13:

Drotaverine CR formulation granules prepared by Wet Granulation method (240 mg

strength)

IR Portion CR Portion Ingredients (in mg) (in mg)

Intra-granular Material

Drotaverine HCI HCl 60.00 60.00 180.00

Sodium Starch Glycollate 7.00

24.30 24.30 188.20 MCC HPMC K 100M - 38.40

HPMC K 4M - 38.40

Colloidal Silicon Dioxide - 2.00

Colouring agent 0.20 -

Binder Solution

IPA q.s. q.s.

WO wo 2021/181262 PCT/IB2021/051942

PVP K 30 9.00 25.00

Extra-granular Material

18.00 5.00 MCC MCC Colloidal Silicon Dioxide 0.45 1.00

Colouring agent 0.15

Magnesium Stearate 0.90 2.00

EXAMPLE 14:

Drotaverine CR formulation granules prepared by Wet Granulation method (240 mg

strength)

IR Portion CR Portion Ingredients (in mg) (in mg)

Intra-granular Material

Drotaverine HCI HCl 75.00 165.00

Sodium Starch Glycollate 7.00

34.80 131.50 MCC HPMC K 100M -I 54.00

HPMC K 4M - 54.00

Colloidal Silicon Dioxide 2.00 -

Colouring agent 0.20 --

Sodium Metabisulfite 0.9 2.1

Binder Solution

Citric Acid 3.6 8.4

IPA IPA q.s. q.s.

PVP K 30 9.00 25.00 25.00

Extra-granular Material

MCC PH 18.00 5.00

Colloidal Silicon Dioxide 0.45 1.00

Colouring agent 0.15

Magnesium Stearate 0.90 2.00

WO wo 2021/181262 PCT/IB2021/051942

EXAMPLE 15:

Drotaverine CR formulation granules prepared by Wet Granulation method (240 mg

strength)

Ingredients IR Portion CR Portion

(in mg) (in mg)

Intra granular Material

Drotaverine HCI HCl 75.00 165.00

Crospovidone 10.00

31.80 131.50 MCC HPMC K 100M - 80.00

HPMC K 4M - 28.00

Colloidal Silicon Dioxide - 2.00

Colouring agent 0.20 -

Sodium Metabisulfite 2.0 2.1

Binder Solution

Maleic Acid 2.5 8.4

IPA q.s. q.s.

PVP K 30 15.00 25.00 25.00

Extra-granular Material

12.00 5.00 MCC Colloidal Silicon Dioxide 0.45 1.00

Colouring agent 0.15

Magnesium Stearate 0.90 2.00

WO wo 2021/181262 PCT/IB2021/051942

EXAMPLE 16:

Drotaverine CR formulation granules prepared by Wet Granulation method (240 mg

strength)

Ingredients IR Portion CR portion

(in mg) (in mg)

Intra granular Material

Drotaverine HCI 75.00 165.00

Crospovidone 10.00

31.80 131.50 MCC HPMC K 100M - 50.00

58.00 HPMC K 4M -

Colloidal Silicon Dioxide - 2.00

Colouring agent 0.20 -

Butyl hydroxy Toluene 1.0 2.1

Binder Solution

Tartaric acid 3.5 8.4

IPA q.s. q.s.

PVP K 30 15.00 25.00

Extra granular Material

12.00 5.00 MCC Colloidal Silicon Dioxide 0.45 1.00

Colouring agent 0.15

Magnesium Stearate 0.90 2.00

EXAMPLE 17:

Drotaverine CR formulation granules prepared by Wet Granulation method (240 mg

strength)

WO wo 2021/181262 PCT/IB2021/051942

Ingredients IR Portion CR portion

(in mg) (in mg)

Intra granular Material

Drotaverine HCI 75.00 75.00 165.00

Crospovidone 10.00

31.80 131.50 MCC HPMC K 100M - 50.00

58.00 HPMC K 4M -

Colloidal Silicon Dioxide - 2.00

Colouring agent 0.20 -

Butyl hydroxy Toluene 1.0 2.1

Binder Solution

Tartaric acid 3.5 8.4

IPA q.s. q.s.

PVP K 30 15.00 25.00

Extra granular Material

12.00 5.00 MCC Colloidal Silicon Dioxide 0.45 1.00

Colouring agent 0.15

Magnesium Stearate 0.90 2.00

EXAMPLE 18:

Drotaverine CR formulation MUPS (Multiple-Unit Pellet System) tablets (240 mg

strength)

MUPS Tablets Qty. Per unit

Ingredients (in mg)

HCI Drotaverine HCl 240.00

PCT/IB2021/051942

12.00 HPMC Polysorbate -80 12.00

Citric Acid 6.00

Talc 5.00

Sugar Spheres 355-425 um 80.00

Ethyl Cellulose Coating dispersion 20.00

Microcrystalline Cellulose (MCC) 173.00

Magnesium Stearate 4.00

Colloidal Silicon Dioxide 4.00

EXAMPLE 19:

Drotaverine CR formulation capsules with CR pellets (240 mg strength)

Capsule with CR Pellets

Qty. Per capsule

Ingredients (in mg)

Drotaverine HCI 240.00

12.00 HPMC Polysorbate -80 12.00

Fumaric Acid 5.00

Butyl Hydroxy Anisole 3.00

Talc 5.00

Sugar Spheres 355-425 um 80.00

Ethyl Cellulose Coating dispersion 20.00

Starch 15.00

Stearic Acid 4.00

Colloidal Silicon Dioxide 4.00

WO wo 2021/181262 PCT/IB2021/051942

In-vitro dissolution profile

The formulations of the present invention are illustrated in but not limited to the

examples given hereinabove. A representative drug dissolution release rate profile for an

exemplary formulation of the present invention is depicted in Figure 1. The developed

formulation is evaluated for 'In-vitro dissolution profile' using USP II Method, at 75 rpm,

in 1000 ml, 0.1 N HCI (pH 1.2), at 37=0.5° C. The dissolution release profile of CR

formulations of the present invention in-vitro is found to be between about 25% and about

40% released after about 1 hour, between about 30% and about 50% released after about 2

hours, between about 40% and about 65% released after about 4 hours, and between about

60% and about 85% released after about 8 hours and NLT about 85% after about 16 hours.

Chemical Stability:

Impurities in new drug products such as degradation products of the drug substance

or reaction products of the drug substance with an excipient and/or immediate container

closure system are collectively referred to as "degradation products". Generally, impurities

present in the new drug substance need not be monitored or specified in the new drug

product unless they are also degradation products.

The present invention provides stable CR formulations of Drotaverine or salt

thereof or similar active agents which are prone to oxidative / hydrolytic degradation. The

developed formulations have improved chemical stability wherein individual unknown

impurity levels are less than 0.2%w/w (as per currently available globally acceptable

standards for drug products).

Non-limiting advantages of the CR formulations of the present invention:

1. The CR formulations of Drotaverine, developed by extensive trials and developing ef-

fective ratios of polymers, binders, excipients vis-à-vis active drug, achieve a target

drug release rate from a single ingestible dosage form and achieves maintenance of a

target MEC for about 24 hours.

2. The CR formulations disclosed herein are designed to achieve an immediate onset of action and sustained release profile. For instance, a sufficient (therapeutic) amount of the Drotaverine drug is released within about 1 hour after administration to achieve plasma levels similar to an immediate release dosage form and the rest of the drug is 5 gradually released over a period of about 12-24 hours to maintain the drug concentration within the therapeutic window. 2021235395

3. The CR formulations of Drotaverine are capable of being formulated as single or multi- layered tablets or multicoated mini-tablets, pellets or beads filled in capsules. 10 4. The formulations of Drotaverine are capable of being manufactured by direct compression, dry granulation, wet granulation or fluidized bed processing methods.

Other embodiments of the invention will be apparent to those skilled in the art from 15 consideration of the specification and practice of the embodiments disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims. In addition, where this application has listed the steps of a method or procedure in a specific order, it may be possible, or even expedient in certain circumstances, to change the order in which some 20 steps are performed, and it is intended that the particular steps of the method or procedure claims set forth herein below not be construed as being order-specific unless such order specificity is expressly stated in the claim. In the claims which follow and in the preceding description of the invention, except where the context requires otherwise due to express language or necessary implication, the 25 word “comprise” or variations such as “comprises” or “comprising” is used in an inclusive sense, i.e. to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the invention.

43 21982198_1 (GHMatters) P119866.AU 12/08/2025

Claims

We Claim:

1. A formulation comprising a controlled-release portion and an immediate-release portion, wherein the formulation comprises Drotaverine or a salt thereof, a polymer 5 or mixture of polymers, and at least one pharmaceutically acceptable excipient, wherein said formulation comprises at least one acidifying agent and from 0 to 10% by weight of anti-oxidants. 2021235395

2. The formulation of claim 1, wherein the polymer or mixture of polymers is selected 10 from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), ethyl cellulose, methacrylic acid-ethyl acrylate copolymer, polyethylene oxides (PEO), and a combination thereof, and wherein the formulation has a dissolution release profile in vitro of 25% to 40% after about 1 hour, 30% to 50% after about 2 hours, 40% to 65% after about 4 hours, 60% 15 to 85% after about 8 hours and not less than about 85% after about 16 hours.

3. The formulation of claim 1 or 2, wherein said at least one acidifying agent is selected from the group consisting of Citric acid, Fumaric acid, Lactic acid, Maleic acid, Malic acid, Tartaric acid, and a combination thereof. 20

4. The formulation of any one of claims 1 to 3, wherein the formulation releases Drotaverine or salt thereof for at least 24 hours.

5. The formulation of any one of claims 1 to 4, wherein the formulation comprises about 25 10 to about 300 mg of Drotaverine or salt thereof.

6. The formulation of claim 5, wherein the formulation comprises Drotaverine or salt thereof in the range of 15% to 60% (w/w) of the formulation.

30 7. The formulation of any one of claims 1 to 6, wherein the Drotaverine salt is Drotaverine hydrochloride.

8. The formulation of any one of claims 1 or 3 to 7, wherein the polymer or mixture of polymers is selected from the group consisting of hypromellose, hydroxyethyl

44 22144598_1 (GHMatters) P119866.AU 15/10/2025

cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), carboxymethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose or salts thereof, ethyl cellulose, carbomers, methacrylic acids based polymers, polyethylene oxides (PEO), 5 and a combination thereof.

9. The formulation of any one of claims 2 to 8, wherein the polymer is polyethylene 2021235395

oxide (PEO).

10 10. The formulation of any one of claims 2 to 8, wherein the polymer or mixture of polymers is hydroxypropyl methylcellulose having an apparent viscosity ranging from about 100-150,000 cP, wherein, optionally, the polymer or mixture of polymers is K100, K4M, K15M, K100M, E4M, E10M, Methocel K100M CR, or a combination thereof. 15 11. The formulation of any one of claims 1 to 10, wherein the formulation comprises controlled-release polymer in the range of 5% to 30% (w/w) of the formulation.

12. The formulation of any one of claims 1 to 11, wherein the at least one 20 pharmaceutically acceptable excipient is selected from the group consisting of gums, fillers, flow aids, lubricants, disintegrants, diluents, binders, lubricants, glidants, and a combination thereof.

13. The formulation of claim 12, wherein: 25 the gums are selected from the group consisting of xanthan gum, karaya gum, locust bean gum, alginic acid, sodium alginate, acrylic polymers, and a combination thereof; the diluents are selected from the group consisting of microcrystalline cellulose, lactose, dicalcium phosphate, starch, and a combination thereof; 30 the binders are selected from the group consisting of starch, polyvinylpyrrolidone, natural or synthetic gum, cellulosic polymers, and a combination thereof;

45 22144598_1 (GHMatters) P119866.AU 15/10/2025

the lubricants and glidants are selected from the group consisting of talc, colloidal silicon dioxide, magnesium stearate, and a combination thereof; and the disintegrants are selected from the group consisting of Sodium Starch Glycollate, Croscarmellose Sodium, Crospovidone, and a combination thereof. 5

14. The formulation of any one of claims 1 to 13, wherein the formulation is for oral delivery. 2021235395

15. The formulation of claim 14, wherein the formulation is a tablet, mini-tablet, MUPS 10 (Multiple-Unit Pellet System) tablet or capsule.

16. The formulation of claim 15, wherein the formulation is in the form of single layered, bi-layered, multi-layered, coated, uncoated, or multi-coated pellets, granulates, or beads, which can be filled into capsules or compressed to tablets. 15

17. The formulation of any one of claims 1 to 16, wherein the formulation comprises a functional or non-functional coating.

18. The formulation of any one of claims 15 to 17, wherein the tablet or capsule is 20 prepared by a wet granulation, dry granulation/slugging or direct compression process.

19. The formulation of any one of claims 15 to 18, wherein the capsule comprises shells prepared by gelatin or non-gelatin based materials. 25

20. The formulation of any one of claims 2 to 19, wherein the formulation elicits a minimum effective concentration in plasma of a subject similar to immediate release dosage form within about 1 hour and the rest of the drug is gradually released over a period of about 12-24 hours to maintain the drug concentration within the therapeutic 30 window of Drotaverine.

21. A method of preparing a single-layer controlled release tablet comprising Drotaverine or a salt thereof, the method comprising:

46 22144598_1 (GHMatters) P119866.AU 15/10/2025

(a) sieving and dry mixing Drotaverine or salt thereof with an acidifying agent, polymer and excipient to obtain a drug-excipient blend; (b) sieving and mixing extra-granular ingredients with the drug-excipient blend to obtain a formulation; 5 (c) compressing the formulation to form the tablet.

22. A method of preparing a single or multi-layer tablet comprising Drotaverine or a salt 2021235395

thereof, the method comprising: (a) sieving and dry mixing Drotaverine or salt thereof with an acidifying agent, 10 polymer and excipient to obtain a dry mix; (b) granulating the dry mix with a binder solution comprising at least polyvinylpyrrolidone and isopropyl alcohol to obtain granules; (c) drying the granules to obtain a desired Loss-on Drying of the dried granules; (d) milling the dried granules followed by sieving to obtain granules of specific 15 size; (e) sieving extra-granular ingredients followed by mixing with the granules of specific size to obtain a formulation; and (f) compressing the formulation to form the tablet.

20

23. The method of claim 21 or 22, further comprising coating the tablet with one or more functional or non-functional coatings.

24. A method of treating at least one symptom of gastrointestinal, biliary, urological and gynecological disorders characterized by spastic conditions of smooth muscles, 25 optionally, irritable bowel syndrome, biliary colics, cholecystolithiasis, cholecystitis, cholangitis, renal colics, nephrolithiasis, ureterolithiasis, pyelitis, cystitis, dysmenorrhoea, imminent abortion, or uterine tetanus in a subject in need thereof, comprising administering to the subject the formulation of any one of claims 1 to 20.

30

25. The method of claim 24, wherein the formulation is administered as single layer, bi- layered, multi-layered, uncoated, coated or multicoated pellets, beads, or granules in tablet or capsule form.

47 22144598_1 (GHMatters) P119866.AU 15/10/2025

2021235395 16 Oct 2025

26. Use of Drotaverine or a salt thereof, a polymer or mixture of polymers, and at least one pharmaceutically acceptable excipient in the manufacture of a controlled-release formulation according to any one of claims 1 to 20 for treating at least one symptom of a gastrointestinal, biliary, urological or gynecological disorder characterized by 55 spastic conditions of smooth muscles in a subject. 2021235395

48 48 22147415_1 (GHMatters) P119866.AU

120 Drotaverine CR Dissolution Profile

100 % Drug Released

80

60 DTV-11

40

20

0 0 4 8 12 16 16 20 24 Time in hours

Figure 1

1/1